The University of Pittsburgh Brain Trauma Research Center has been investigating the molecular and cellular mechanisms of secondary brain injury (physiologic and neurochemical responses of the injured brain) since its inception in 1991. Our studies have lead to an improved understanding of specific molecular mechanisms likely to be responsible for early and delayed neurologic dysfunction following TBI. The investigators of the Center have resulted in more than 188 peer-reviewed journal articles and book chapters during the last five years. TBI initiates pathological biochemical cascades that can persist long after survival. An increased understanding of the mechanisms of these cascades and their attenuation by translatable therapies are the primary scientific goals of our program project. The specific projects selected for this proposal represent a logical extension of the research conducted by primary investigators of the previous program project grant, as well as a new area of exploration introduced by Dr. C. Edward Dixon. These include the study of (1) nitrosative stress and PARP activation, (2) statins therapies and their interaction with AB in cell death, (3) effects of calcineurin inhibition on neuronal death and plasticity, (4) Fas-mediated cell death, and (5) mechanism(s) underlying the endogenous beneficial effects of iNOS. All of the projects include clinically relevant time points, translatable treatments, and at least one specific aim that test the relevance of the basic science hypotheses to TBI in humans. Because of this we will be able to correlate the findings of our primary investigations with human TBI and determine their relative importance in effecting neurologic outcome. In this way, the completion of our specific aims can be expected to define critical acute and chronic molecular mechanisms of secondary brain injury and identify treatments most likely to be beneficial to TBI patients.